Drug metabolism Flashcards
What is the function of drug metabolism?
It is reponsible for converting lipophilic drugs to more hydrophilic compounds to facilitate their excretion
What is Drug metabolism?
A biochemical modification of pharmaceutical substances by living organisms, usually through enzymatic activity
What happens to lipid soluble substances in the kidney?
They are reabsorbed
Where are the Metabolizing enzymes present?
Liver, intestine and
blood
In a low portion on lungs
What is the function of the reactions in metabolism?
Increasing water solubility
What are the functions of drug metabolism?
- The major elimination pathway of drugs from the body
- Evolved to deal with environmental toxins
- Limits the life of a substance in the body
- Promotes excretion and reduces binding affinity for biological targets
What could happen if active metabolism are produced?
Side effects may occur or may be useful for the use of prodrugs
How many phases drug metabolism have?
Phase I, II and perphaps 3
What are the type of reactions that may happen in Phase I metabolism?
Introduces or exposes polar functional groups
Provides sites for Phase II metabolism
Addition or unmasking of: -OH, -NH2, -SH, -COOH, etc..
Where does Phase I metabolism reactions happen?
Occurs in most tissues
Primary “first pass” site of metabolism occurs during hepatic circulation
Also in gastrointestinal epithelial, renal, skin and lung tissues
Where does Phase I metabolism reactions happen (subcellular distribution)?
Most phase I enzymes are located in the endoplasmic reticulum
Enriched in microsomal preparations
Describe the phase I of metabolism. Include
- Reactions
- Hydrophilicity
- Mechanism
- Consequence
Phase I include hydrolysis, oxidation and reduction reactions. The increase in hydrophilicity is small, mechanism focus on creates functional group. Consequence, Facilitates excretion Primes
for phase II
Describe the phase II of metabolism. Include
- Reactions
- Hydrophilicity
- Mechanism
- Consequence
Phase II include conjugate reactions. The increase in hydrophilicity is large, mechanism focus on polar group added to
functional group. Consequence, Facilitates excretion.
Describe Phase II metabolism reactions
- Reactions are generally synthetic
- Almost always result in loss of biological activity
- Involves conjugation of functional groups with hydrophilic endogenous substrates
What types of groups are added during phase II metabolism and why are they added?
- Small, polar groups: glutathione, glucuronic acid, sulfate, methyl, amines/amino acids, etc..
- Increases hydrophilicity
- Conjugates are water soluble and readily excreted from the body
What types of enzymes are involved in phase II metabolism
Specify reaction and enzyme involved
- Glucuronidation - UDP-glucuronosyltransferase (UGT)
- Sulfation - sulfotransferases
- Glutathione (GSH) conjugation - glutathione S-transferases
- Acetylation - N-acetyltransferases
- Methylation - methyltransferases
What are the principal phase I enzymes?
– Cytochrome P450 (CYP) (in the liver)
– Flavin monooxygenase
– Monoamine oxidase
– Esterases
– Amidases
– Hydrolases
– Reductases, dehydrogenases, oxidases
What are the most common enzyme where the drug is metabolized in phase I and Phase II?
Phase I: CYP specific CYP3A4/5/7
Phase II: UGT
The are specific polymorphisms that may be clinically relevant. Mention the enzyme and the gene that may be affected by this
CYP: cytochrome P450
NQ01: NADPH:quinone oxidoreductase (DT diaphorase)
DPD: dihydropyrimidine dehydrogenase
ADH: alcohol dehydrogenase
ALDH: aldehyde dehydrogenase
Give some example of the drug-metabolizing enzymes that exhibit clinically
relevant genetic polymorphisms
– GST: Glutathione-S-Transferases
– ST: Sulfotransferase
– HMT: histamine methyltransferase
– COMT: catechol O-methyltransferase
– TPMT: thiopurine methyltransferase
– UGT: UDP-Glucuronosyl-S-Transferases
What assay may be used to identify metabolites produced during metabolism?
Microsome or hepatocyte assay coupled with LC-MS to identify major metabolites
What questions should be asked when you identify certain metabolites for phase II metabolism
– What metabolites are formed?
– Are they active?
– Are they reactive/toxic?
* Should these be considered in a Target Product Profile?
What are “soft drugs”?
Projected to be safer drugs with an increased therapeutic index
– Limit the duration of action by integrating metabolic liabilities into the drug
What happens after absorption to soft drugs?
They are rapidly metabolized to components that are quickly eliminated from the body
Undergo predictable, “controllable” metabolism to nontoxic and
inactive metabolites
– Generally avoid oxidative metabolism
– Use hydrolytic enzymes to achieve predictable and controllable drug
metabolism
* Commonly plasma and tissue esterases
what is a hard drug and how it is excreted?
Hard drugs are non- metabolisable drugs- usually to liphophilic.
1.Simplified pharmacokinetics
- Excreted primarily through bile or kidney unchanged
2. Removes toxicity due to reactive or active metabolites
Give 2 example of hard drugs
-Zoledronic acid (osteoporosis)
-Lisinopril (hypertension)
What is Atracurium?
- A nicotinic acetylcholine receptor antagonist
– A non-depolarizing muscle relaxant used during surgery or mechanical ventilation
– Requires fast recovery time - Undergoes spontaneous Hoffman elimination and ester hydrolysis at
physiological pH
Describe Remifentanil
- Novel, short-acting -opioid receptor agonist used during surgery
– Rapid onset and recovery time - Undergoes rapid hydrolysis by non-specific tissue and plasma
esterases to remifentanilic acid
– 1/4600th the potency of remifentanil - Half-life remains at 4 min, even after a 4 h infusion
What is the purpose of a prodrug?
Most common reason to use a pro-drug approach is to increase
oral absorption and hence F
What are active metabolites?
Result when a drug is metabolised into a modified form that continues to produce effects in the body.
When are the active metabolites formed? Give an example
Pharmacologically active metabolites are generally formed by phase I
oxidative reactions
Example
- Acetaminophen (paracetamol) is an O-deethylated metabolite of phenacetin
– Superior analgesic activity with fewer side-effects
However, in phase II conjugation reactions can also produce biologically active metabolites- better
safety profiles
Example
-Morphine 6-glucuronide is more potent as a -opioid receptor agonist than
morphine
Where does conversion of a prodrug happen in the body?
Conversion of pro-drug to active metabolite can occur in small
intestine or liver (plasma, lung)
What are the desired characteristics of a prodrug?
– Limited target engagement
– Rapid hydrolysis to the active compound
– High target engagement of the active compound (primary metabolite)
– No pharmacological effect of secondary metabolites
What are the reactions that are include to form pro-drugs?
-Esterification
– Hydrolysis
– Phosphorylation
– Oxidation
– Reduction
What model could be used to describe metabolite kinetics
Two compartment model for metabolite kinetics
– Compartment models can also be used to evaluate metabolite
kinetics
Give an example of pro-drugs. How is it form?
– Pivampicillin, talampicillin, and bacampicillin are pro-drugs of ampicillin
(BAV < 50 %)
– All result from the esterification of the polar carboxylate group to form
lipophilic, enzymatically labile esters (F = 98-99 %)
Why is it important to understand the kinetics of drug metabolites?
– Can be very important to understand
* Potency of metabolites – prodrugs for example
– Need to consider metabolites for secondary pharmacology
– Understanding metabolite kinetics is also of great importance in
toxicology
What is fm and k.fm in the image? what type of model it represent? and which is the plasma compartment?
fm: A fraction of the drug
k.fm: rate constant
Parent drug is the center compartment- plasma compartment.
Describe two compartment model for metabolite kinetics
What compartments, equations and assumptions
= (parent → metab) – elimination
= 𝑘. 𝑓𝑚. 𝐴𝑏 − 𝐴𝑚. 𝑘𝑚
- NB Assume that metabolite and parent are both
excreted by the same route
->elimination of parent
= total elimination (i.e. elimination of converted +
elimination of non-converted)
What is the cofactor of cytochrome P450?
Haem
What is the absorbance of CYP450?
Mention why the absorbance is at that specific wavelenght
They have an unusual absorbance maximum at 450 nm upon C=O binding to the reduced form (Fe2+) of the haem
– This led to the initial P450 designation
* P is for pigment
* Other haem proteins have λmax at 420 nm
* Absorbance at 450 nm is due to an unusual
fifth ligand to the haem: a cysteine-thiolate
Mention 3 examples of CYP450 families, its function and some of their names
- CYP1
Drug and steroid (especially estrogen) metabolism,
benzo[a]pyrene toxification
3 subfamilies, 3 genes, 1 pseudogene
CYP1A1, CYP1A2, CYP1B1 - CYP2
Drug and steroid metabolism 13 subfamilies, 16 genes, 16 pseudogenes
CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1 - CYP3
Drug and steroid (including testosterone) metabolism 1 subfamily, 4 genes, 2 pseudogenes
CYP3A4, CYP3A5, CYP3A7, CYP3A43
Explain each color letter of the image.
Cytochrome P450
has more than 50
enzymes, six of them metabolize 90 % of drugs. Which are the most significant?
Two most significant enzymes are CYP3A4
and CYP2D6
Who do CYP450 affect drug-drug interactions?
Many drugs may increase (or induce) or decrease (or inhibit)
the activity of various CYP isozymes
* For example, if drug A inhibits the CYP-mediated metabolism
of drug B, drug B may accumulate within the body to toxic
levels
* These drug interactions may necessitate dosage adjustments
or choosing alternative drugs that do not interact with the CYP
system
What is the main reaction that is catalyzed by CYP450?
- Primarily mono‐oxygenation
– One atom of oxygen is incorporated into a substrate
– The other is reduced to H2O with reducing equivalent derived from NADPH
RH + O=O + H+ + NADPH => ROH + H2O + NADP+
What are the function of Cytochrome P450?
Cytochrome P450 are involved in metabolism of diverse endogenous compounds. Also essential for the metabolism of many
medicinal drugs.
What are the CYP450 reactions involved in Phase I metabolism?
- Hydroxylation of an aliphatic or aromatic carbon
- Epoxidation of a double bond
- Heteroatom (S-, N-) oxidations
- Heteroatom (O-, S-, N-) dealkylation
- Oxidative group transfer
- Cleavage of esters
- Dehydrogenation
What are the 3 important CYP450 activities?
- Significant divergence across species
2.Concentrated in the liver: extrahepatic enzyme activities also contribute to patho/physiological
process
3.Located in microsomes: Possibility to perform detailed metabolic studies in vitro using human microsomes
Possibility to perform detailed metabolic studies in vitro using human microsomes. Give 2 examples.
1.CYP2B6 induced by phenytoin
2. CYP1A2 induced by broccoli
Some drugs can inhibit CYP isoforms. Provided 2 examples.
-CYP2C8 inhibited by gemfibrozil
– CYP3A4, 5 & 7 are inhibited by grapefruit juice
What happens in carbon hydroxilation?
- Metabolic liability related to ease of hydrogen atom abstraction
and energy of resulting radical (= lower bond strength) - Adjacent benzyl group stabilises radical through delocalisation
- Can occur due to orbital overlap
Explain CYP450 Carbon hydroxylation.
Carbon hydroxylation, also known as C-oxidation
– Insertion of oxygen into a C-H bond
* Formation of alcohols
– Primary alcohols easily oxidized to carboxylic acids
Give the name and explain the following reaction.
Carbon hydroxylation, also known as C-oxidation.
-Generally accepted mechanism involves hydrogen atom abstraction
by (FeO)3+ followed by oxygen insertion (radical recombination)
What is the use of epoxides (generated by CYP450)?
- Epoxides are key intermediates in the hydroxylation of
aromatic rings - The epoxide intermediate can react with a range of
endogenous nucleophiles eg GSH, proteins
What is the use of arene oxides or epoxides (generated by CYP450)?
- Epoxides are key intermediates in the hydroxylation of
aromatic rings - The epoxide intermediate can react with a range of
endogenous nucleophiles eg GSH, proteins
What are arene oxides or epoxides?
Main characteristics
- Relatively unstable intermediates in metabolic chemistry and
are not usually isolated - Rapidly transformed to phenols, dihydrodiols or GSH
conjugates dependent on the electronic properties of the
substrate
true or false, alkyl sites are more labile than enzylic/allylic sites
False
How many bile salts are produced by the liver in a day?
- The liver produces 500-600 mg bile salts/day
Where are bile salts secreted to form bile? What is its function?
- Secreted into the bile duct to form bile
– Neutralises acid chyme in the duodenum
– Emulsifies fats for digestion by pancreatic lipase
Which enzyme is associate with the Convertion of cholesterol into 7alpha-hydroxycholesterol?
CYP7A1 associated with liver microsomes converts cholesterol into 7alpha-hydroxycholesterol
What is the process that cholesterol goes through by CYP450s?
*Oxidation of cholesterol by CYP450
Mainly cholic acid and deoxycholic acid
Which enzyme is associate with the following process?
The enzyme associate is CYP8A1: PGI2 synthase
-Extrahepatic CYP450- Associated with endothelium microsomes
What is CYP5A1: TxA2 synthase and what is its function?
- Extrahepatic CYP450
- Associated with platelet microsomes
- Converts PGH2 to thromboxane A2
Where is CYP11A1: P450scc found and what is its function?
- Mitochondrial CYP450
- Associated with adrenal cortical steroidogenesis
Why is CYP11B2: Aldosterone synthase important?
It is associated with adrenal cortex
What is the function of Flavin monooxygenase?
- Heteroatom (S-, N-) oxidation
- Formation of N-, S-oxides or hydroxylamines (primary and
secondary amines) by FMO (or CYP450) - Many oxides are less toxic, but N-oxygenation of arylamines
and heterocyclic amines is an important bio-activation step - Generally accepted mechanism involves abstraction of an
electron from the heteroatom by (FeO)3+ followed by oxygen
insertion
Give an example of FMO activity and Heteroatom (S-, N-) oxidation
What are the reactions involved in Phase II metabolism?
- Conjugation of functional groups
with hydrophilic endogenous
substrates
– Small, polar groups
Glutathione
Glucuronic acid
Sulfate
Acetyl
Methyl
Amines/amino acids
etc.. - Increases hydrophilicity
– Conjugates are water soluble and
readily excreted from the body - Glucuronidation
- Glutathionylation
- Sulfation
- Acetylation
- Methylation
- Glycylation, taurylation
Mention characteristics of the structure of UGTs
- 1TM proteins with catalytic site in ER lumen
– UDP-glucuronic acid transporter (SLC35D1)
What are the functions of flavin monooxygenase
flavin adenine dinucleotide (FAD) are utilised to oxidise its substrates
– Mixed function amine oxidase
* Oxidises a wide array of heteroatoms, particularly soft nucleophiles, such
as amines, sulfides, and phosphites
What is the function of UGTs?
- Form O-, N-, S-, C- glucuronides
– Water-soluble products more rapidly excreted in bile or urine
– Undergo molecular recognition by transporters
Where Flavin monooxygenase are located?
Located in smooth ER
– Enriched in:
* Human, pig, rabbit liver
* Guinea-pig lung
* Human kidney
Why is glucuronidation important?
Physiologically, glucuronidation is important for clearance of
bilirubin, steroids and 5-HT
Are drug glucuronides active?
Inactive, but there are some exceptions
– Morphine 6-glucuronide 3x potency of morphine
Name the following reaction
Heteroatom (S-, N-) oxidation
Mention examples of glucuronide substrates
– Morphine, p-nitrophenol, valproic acid, NSAIDS, bilirubin, steroid
hormones
Mention examples of inducers of glucuronidation
- Inducers include
– Phenobarbital, indoles, 3-methyl cholanthrene, cigarette smoking
What are the factors that affect the rate of glucurodination?
- Age
- Infant (increase glucurodination)
-Eldery (increase glucurodination or unchanged) - sex
- Females (Decrease glucurodination)
-males (increase glucurodination)
Mention the relatin between glucuronidation and potency ffor target drugs.
Increased rate of glucuronidation results in a loss of potency for the target drugs or compounds.
Mention examples of syndromes that occur when there is genetic variation in UGT1A1
- Gilbert’s syndrome (mild):
– Loss-of-function mutation
Reduced enzyme activity
Mild hyperbilirubinemia (often asymptomatic)
Phenobarbital increases rate of bilirubin glucuronidation to normal - Crigler-Nijar syndrome (severe):
– Loss-of-function mutation
Inactive enzyme
Severe hyperbilirubinemia
Inducers have no effect
Mention an example of a drug affected by glucuronidation
Salicylic acid
What functional groups are affected by glucuronidation
- Phenols
- Carboxylic acids
What is Acetylation?
Pathway of xenobiotic biotransformation
* Characterized by the transfer of an acetyl moiety
– Co-substrate acetyl coenzyme A
– The accepting chemical group is a primary amino function
-Acetylation masks an amine with a non-ionisable group
* Products are less water soluble than the parent compound
What is sulfonidation?
- Sulfoconjugation or sulfonation
– Consists of transfer of a sulfonate group to a substrate by multiple sulfotransferases (SULTs)
Mention the principle enzymes on phase II reactions.
– Methyltransferases
– Sulfotransferases
– N-Acetyl transferases
– UDP-glucuronosyltransferases
– Glutathione S-transferases
– N-Acyltransferases
Mention examples of enzymes that catalyze sulfonation and what groups do they target
SULTs are cytosolic enzymes
– PAPS as co-substrate
– Target –OH, -NH2 groups
– SULT1E1
* Estrone sulfate
– SULT2A1
* Sulfoglycolithocholate
What are the substrates of Glutathionylation
- Substrates include an enormous array of electrophilic
xenobiotics (or xenobiotics biotransformed to electrophiles) - Substrates for GSTs share 3 common features:
– Hydrophobic
– Electrophilic
– React non-enzymatically with GSH at a measurable rate
Mention the Co-enzymes/factors on phase II reactions
-S-Adenosyl-L-methionine (SAM)
– 3’-Phosphoadenosine-5’-
phosphosulphate (PAPS)
– Acetyl co-enzyme A
– UDP-D-glucuronic acid
– Glutathione (GSH, γ-L-glutamyl-Lcysteinylglycine)
– Glycine, taurine, L-glutamate
What is the concentration of GSH in the liver?
- The concentration of GSH is very high in liver (3-10 mM) and
GST makes up 10 % of total cellular protein
What are major substrates of methylation?
- Major substrates
– Small endogenous compounds, eg neurotransmitters
– Macromolecules eg nucleic acids
Which are the 4
subfamilies in human of UGTs and where is expressed?
UGT1, UGT2, UGT3 & UGT8
* Expressed in all major organs (ie intestine,
kidneys, brain, adrenal gland, spleen, thymus)
Why is it methylation different from other conjugations?
Mention exceptions
It generally decreases water solubility of the parent compound
– Two notable exceptions
* N-methylation of pyridine-containing xenobiotics (eg nicotine), which
produces quaternary ammonium ions (more water soluble and readily
excreted)
* S-methylation of thioethers to form a positively charged sulfonium ion
What is Deglucuronidation?
Glucuronides may be hydrolysed by β-glucuronidase in the gut
– Enterohepatic Recirculation
– Can lead to prolonged exposure to drugs
Which groups may be affected by NAT 1 or NAT 2 and acetyl co enzyme 1
OH, SH and NH2
What are reactive metabolites?
Drug metabolites that may interact with DNA or proteins
Mention examples of drugs or compounds that may react with DNA and consequences of it
- React with DNA (eg benzidine, safrole)
– Mutagenicity
– Carcinogenicity
– Teratogenicity
What is Glutathionylation mechanism of action?
Glutathione S–transferases (GSTs)
– Nucleophilic attack of reduced glutathione on lipophilic compounds
containing an electrophilic atom (C–, N– or S–)
Mention examples of drugs or compounds that may react with proteins and consequences of it
- React with proteins
– Target organ toxicity (reproducible or idiosyncratic) - eg paracetamol, diclofenac
– Immune hypersensitivity reactions (idiosyncratic) - eg penicillins, halothane
Why considering rective metabolites is important?
- An important cause of drug-induced illness and fatality
– Can cause Drug-Induced Liver Injury (DILI) - A major concern for scientific community and regulators
- Low-dose drugs cause fewer/no problems
What are the possibles routes for The more polar glutathione conjugates in glutathionylation?
The more polar glutathione conjugates are eliminated into the bile or are subsequently subjected to other metabolic steps eventually leading to formation of mercapturic acids.
what is Methylation and its process?
A common but relatively minor pathway of xenobiotic
biotransformation
* Transfer of a methyl group to a substrate by any of several types of methyltransferases.
Give 2 examples of Methylation.
– Catechol-O-methyltransferase (COMT)
– Phenol-O-methyltransferase (POMT)
Which Phase I or Phase II is more prone to cause reactive metabolites?
Phase I reactions
– Oxidative, reductive (-NO2), and hydrolytic pathways, most common cause of RMs
Mention the major routes of paracetamol metabolism
– Glucuronidation (44-55 %) by UGT1A1
and UGT1A6
– Sulfation (20-30 %) by SULT1A1
– N-hydroxylation and dehydration
(CYP2E1, CYP3A4), followed by GSH
conjugation (< 15 %)
* CYP activity forms NAPQI (N-acetylp- benzoquinone imine), an alkylating metabolite, that is usually irreversibly conjugated with the sulfhydryl groups of glutathione
RMs react with DNA and cellular macromoles. Explain the results of those reaction.
- DNA to initiate genotoxicity
- Cellular macromolecules (proteins) to cause acute toxicity to liver and other
organs
What happens at low doses of paracetamol ingestion?
After low level doses (< 4 g/day), paracetamol is converted to
glucuronide and sulfate conjugates, with minor levels of NAPQI or
excretion unchanged
Mainly Phase II metabolism
What is the key role of RM binding to proteins?
RM binding to proteins plays a key role in initiating idiosyncratic ADRs
What happens if you get a paracetamol overdose
Phase I or II metabolism, and what dose is considered to be overdose
- After a highly toxic dose (> 7-10 g), glucuronidation saturates as
well and higher proportions oxidized to NAPQI via CYP450
metabolism - Excess NAPQI eventually depletes GSH stores and starts to form protein adducts through binding to cysteine groups on cellular proteins → hepatic toxicity
Why is there metabolic variability in opiod metabolism?
What may be the result of this variability?
Several factors contributing to this metabolic variability have been
identified
– Risk of drug interactions with an opioid is determined largely by which enzyme systems metabolise the opioid
– The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease)
* Opioid metabolism results in the production of both inactive and active metabolites
What are Opioid and their use?
Opioids are substances that act on opioid receptors to
produce analgesic-like effects. Medically, they are primarily used for pain relief, including anaesthesia.
Most of the clinically used opioids are relatively selective for µopioid receptors, reflecting their similarity to morphine
Why morphine is mainly administered by IV
It is subject to extensive first-pass metabolism
If taken orally, only 40–50 % of the dose reaches the CNS
Morphine is metabolised primarily in the liver
Give 3 opioid examples, include the main metabolic pathway and active metabolites.
Mention 2 main metabolites from morphine and its effects
- M6G
– Active metabolite
– Relative potency depends on route of administration
– 70-360 times more potent following iv administration
– 1.6-9.0 times more potent following sc administration - M3G
– Inactive metabolite
– Lacks analgesic activity, but it exhibits neuroexcitatory effects in
animals
– may be associated with neurotoxic side effects (myoclonus)
Mention the analgesic effect and side effects of MG6
- M6G has similar analgesic effect to morphine
- Fewer side effects
– Less respiratory depression
– Less sedation were observed in the first 4 h post-operative period
– Significant reductions in incidences of nausea and anti-emetic use
What is Pharmacogenetics ?
The study of how a SINGLE gene influences variability in drug response .
Mention details of Tramadol metabolism
How many metabolites, how many of them have activity and enzymes involve
- Complex metabolism
- 11 metabolites identified from both phase I and phase II metabolism
- Only M1 has analgesic activity
- Formation of many metabolites dependent on CYP2D6 and CYP3A4 activity
What is pharmacogenomics?
The study of how genetic (genome) differences in MULTIPLE genes influence variability in drug response
How is oxycodone metabolized?
Oxycodone is metabolised by CYP2D6 to oxymorphone and by CYP3A4 to noroxycodone
What effects does Noroxycodone have?
Metabolite from oxycodone
- Noroxycodone is a weaker opioid agonist than the parent compound
– Presence of this active metabolite increases the potential for interactions with other drugs metabolized by CYP3A4
Which enzyme shows the largest phenotypical variability among CYPs due to genetic polymorphism?
CYP2D6 shows the largest phenotypical variability among the
CYPs, largely due to genetic polymorphism
Provided distribution of PM and UM phenotypes in terms of population.
PM phenotype
– Prevalence in white populations 6-10 %
– Lower in Asian populations (≤1 %)
– Highly variable in African populations (0-34 %)
* At risk of adverse drug reactions or toxicity at regular doses
* UM phenotype
– Prevalence in white populations 1-7 %
– Greater among Middle Eastern and North African populations, up to 30 %
* Require higher doses to achieve therapeutic plasma concentrations
Mention the four posible phenotypes from the four possible allelic variations of CYP450
Poor metaboliser: Two non-functional alleles
Intermediate metaboliser: At least one reduced function allele
Extensive metaboliser: At least one functional allele
Ultra-rapid metaboliser: Multiple copies/high expression of a functional allele
What are the effects of giving codeine (morphine pro-drug) to poor metabolisers or ultra-rapid metabolisers?
- PM phenotype
– Morphine plasma concentrations undetectable
– Codeine lacks analgesic efficacy - UM phenotype
– Extensive metabolism to morphine
– Increased risk of respiratory depression and other opioid side effects after regular codeine doses
Mention an example of how a SNPs in CYP34 may translate to an effect in vivo
- CYP3A4*17 (F189S) decreased catalytic activity with (eg) testosterone
